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Related Concept Videos

Intrinsically Disordered Proteins02:18

Intrinsically Disordered Proteins

Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

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Related Experiment Video

Updated: Jun 14, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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CDK5-p25 Peptide Inhibitor Samples an Intrinsically Disordered Ensemble in Solution.

Adarsh Ramamurthy1, Kinjal Mondal2, Jeffery B Klauda1,2

  • 1Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742, United States.

The Journal of Physical Chemistry. B
|June 12, 2026
PubMed
Summary
This summary is machine-generated.

The peptide p5, an intrinsically disordered peptide, rapidly interconverts between multiple conformations in solution. This flexibility is key to its selective inhibition of the pathological CDK5-p25 complex in neurodegenerative diseases.

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Neuroscience

Background:

  • The pathological CDK5-p25 complex is implicated in Alzheimer's disease and other neurodegenerative disorders.
  • The peptide p5 selectively inhibits this complex, but its structural basis is unclear.

Purpose of the Study:

  • To characterize the conformational landscape of peptide p5 in aqueous solution.
  • To understand the structural basis for p5's selective inhibition of the CDK5-p25 complex.

Main Methods:

  • Replica exchange with solute tempering (REST2) molecular dynamics simulations (350 ns) with explicit solvent.
  • CHARMM36m force field and Gaussian Mixture Variational Autoencoder (GMVAE) clustering.

Main Results:

  • Peptide p5 exists as an intrinsically disordered peptide in solution, adopting compact, extended, and partially β-structured states.
  • Rapid interconversion between states (nanosecond timescale) due to small free energy differences.
  • Absence of stable helical structure and propensity for transient β-strands suggest a coupled folding-and-binding mechanism.

Conclusions:

  • The conformational flexibility of p5 is crucial for its selective inhibition of CDK5-p25.
  • Findings provide a structural basis for p5's inhibitory mechanism.
  • Lays groundwork for designing improved therapeutic CDK5 inhibitors.